Production intermediate and process for producing pyridine derivative

ABSTRACT

This invention relates to: (1) a compound represented by the formula (V), its tautomer and a mixture of the same; (2) a process for producing the compound represented by the above-mentioned formula (V), its tautomer or a mixture of the same, which comprises reacting N-vinylpiperidone represented by the formula (I) with a nicotinate represented by the formula (II), wherein R represents a lower alkyl group, in the presence of a sodium alkoxide; (3) a process for producing a pyridine derivative represented by the formula (III), which comprises producing the compound represented by the formula (V), its tautomer or a mixture of the same by the process as described in the above (2), and then treating the obtained compound with an acid; and (4) a process for producing a pyridine derivative represented by the formula (IV), in which the treatment with an acid as described in the above (3) is followed by another treatment with a base. Thus, the present invention provides industrial processes for producing pyridine derivatives represented by the formulae (III) and (IV) safely, economically, easily and efficiently without using any hazardous reagents. ##STR1##

This is a 371 of PCT/JP95/01911 filed Sep. 21, 1995.

TECHNICAL FIELD

This invention relates to novel production intermediates to be used forthe production of pyridine derivatives (e.g., anabaseine), which areuseful for the treatment of central nervous system diseases such asAlzheimer's disease and Parkinson's disease, and industrial processesfor producing the same.

BACKGROUND ART

A pyridine derivative represented by formula (III): ##STR2## anabaseinerepresented by formula (IV): ##STR3## and anabaseine derivativesobtained by using the above-mentioned compound (III) or (IV) as asynthesis intermediate are publicly known compounds described in, forexample, Brit. J. Pharmacol., 18, 543 (1962), Agr. Biol. Chem, 26, 709(1962), Toxicon, 9, 23 (1971), Amer. Zoologist, 25, 99 (1985), DrugDevelopment Research, 31, 127 (1994) or 31, 135 (1994), InternationalPublication Nos. WO 92/15306 and WO 94/05288. These compounds are usefulas a remedy for central nervous system diseases such as Alzheimer'sdisease and Parkinson's disease.

As processes for producing the pyridine derivatives represented by theformula (III) and their analogous compounds, there have been publiclyknown some methods with the use of a sodium alkoxides as a base, forexample, (1) a method for producing nicotine by reacting a nicotinatewith N-methylpyrrolidone with the use of sodium ethoxide (Ber., 61., 327(1928)); and (2) another method for producing anabaseine fromN-benzoylpiperidone and ethyl nicotinate with the use of sodium ethoxide(Chem. Ber., 69, 1082-1085 (1936)). However, these methods can achieveonly low yields, i.e., 37.5% and 20.5% respectively. In the method 2!,furthermore, the reaction is accompanied by a rapid increase intemperature, which makes it difficult to control the reactiontemperature. In this case, moreover, 2-phenyl-3,4,5,6-tetrahydropyridineis formed as a side-product which can be hardly eliminated on anindustrial scale. Accordingly, these existing methods are not preferableform an industrial viewpoint.

Subsequently, there have been proposed some methods wherein the sodiumalkoxide is replaced by sodium hydride with an elevated basicity tothereby accelerate the progress of the reaction. Examples of thesemethods include (3) a method for producingnicotinoyl-N-methylpyrrolidone from a nicotinate and N-methylpyrrolidonewith the use of sodium hydride (JP-B-39-25048; the term "JP-B" as usedherein means an "examined Japanese patent publication"); and (4) amethod for producing myosmin from N-vinylpyrrolidone and a nicotinatewith the use of sodium hydride (Acta Chem. Scand., 30B, 93 (1976)).Although these methods contribute to the improvement in yield, theindustrial application thereof is accompanied by serious problems. Thatis to say, the sodium hydride employed as a reagent in these methodsspontaneously ignites when it comes in contact with air. Also, itcatches fire easily in the presence of water. At the reaction, itundergoes vigorous foaming and causes heat generation and evolution ofhydrogen gas. Due to these characteristics, it is highly dangerous touse sodium hydride in the synthesis on a large scale. To ensure thesecurity, therefore, specific devices and techniques are required.Moreover, sodium hydride is usually marketed in a state of beingdispersed in liquid paraffin in an amount of about 60%. Accordingly, theproduction process should involve an additional step of completelyeliminating the liquid paraffin. Thus, it is to be concluded that theabove-mentioned methods with the use of sodium hydride are unsuitablefor industrial purposes from an economical viewpoint too.

Examples of other production methods include (5) a method starting fromN-nicotinoylpiperidone with the use of calcium oxide (Synth. Commun., 2(4), 187-200 (1972)); (6) a method starting from bromopyridine andcyclopentanone with the use of n-butyllithium (Tetrahedron Lett., 24(18), 1937-1940 (1983)); (7) a method wherein bromopyridine is condensedwith N-tert-butyloxycarbonylpiperidone with the use of n-butyllithium(J. Org. Chem., 54 (1), 228-234 (1989)); and (8) a method whereinN-trimethylsilylpiperidone is condensed with a nicotinate derivativewith the use of lithium diisorpopylamide (International Publication WO92/15306). However, it has been clarified that these methods also sufferfrom various problems. Namely, the method (5), wherein the startingmaterial is molten by heating over an open fire in the presence ofcalcium oxide, is highly dangerous and thus unsuitable as an industrialprocess. In the methods (6), (7) and (8), on the other hand, thereactions should be performed at a low temperature (-70° C. or below)with the use of n-butyllithium or lithium diisopropylamide. Thus, thesemethods are not preferable as industrial processes from the viewpointsof economics and safety.

Therefore, it has been urgently required to develop an industrialprocess by which the pyridine derivatives represented by the formulae(III) and (IV) can be produced safely economically, easily andefficiently without using any hazardous reagent.

DISCLOSURE OF THE INVENTION

The present inventors have conducted extensive studies to establish anindustrial process which is excellent in safety, economics, convenienceand efficiency. As a result, they have unexpectedly found out a novelsynthesis intermediate, which is useful for the production of thecompounds (III) and (IV), and a production process with the use of thesame by using a sodium alkoxide with piperidone protected with aspecific N-protecting group, thus completing the present invention.Accordingly, the present invention relates to:

(1) a compound represented by formula (V): ##STR4## its tautomer and amixture of the same;

(2) a process for producing the compound represented by the formula (V),its tautomer or a mixture of the same as described in the above (1),which comprises reacting N-vinylpiperidone represented by formula (I):##STR5## with a nicotinate represented by formula (II): ##STR6##

wherein R represents a lower alkyl group; in the presence of a sodiumalkoxide;

(3) a process for producing the compound represented by the formula (V),its tautomer or a mixture of the same as described in the above (2),wherein said sodium alkoxide is sodium ethoxide;

(4) a process for producing the compound represented by the formula (V),its tautomer or a mixture of the same as described in the above (2),wherein R in the formula (II) is an ethyl group and the sodium alkoxideis sodium ethoxide;

(5) a process for producing a pyridine derivative represented by formula(III): ##STR7## which comprises producing the compound represented bythe formula (V), its tautomer or a mixture of the same by the process asdescribed in any of the above (2), (3) and (4), and then treating theobtained compound with an acid; and

(6) a process for producing a pyridine derivative represented by formula(IV): ##STR8## wherein the treatment with an acid as described in theabove (5) is followed by another treatment with a base.

Now, the present invention will be illustrated by reference to thefollowing reaction scheme. ##STR9##

In the step (a) of the above reaction scheme, publicly known compounds(I) and (II) are reacted in an appropriate solvent in the presence of asodium alkoxide to thereby give a compound represented by the formula(V) or (VI). The compound represented by the formula (V) is3-nicotinoyl-1-vinyl-2-piperidinone, while the compound represented bythe formula (VI) is the tautomer of the same.

The lower alkyl group represented by R in the compound (II) is a linearor branched alkyl group having 1 to 4 carbon atoms. Typical examplesthereof include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl andtert-butyl groups. It is preferable that R represents a methyl or ethylgroup, still preferably an ethyl group.

Examples of the sodium alkoxide usable in this step include sodiummethoxide, sodium ethoxide, sodium propoxide and sodium tert-butoxide.It is preferable to use sodium methoxide or sodium ethoxide, stillpreferably sodium ethoxide, therefor.

The solvent to be used in this step is not particularly limited, so longas it exerts no undesirable effect on the reaction. Examples thereofinclude hydrocarbons such as benzene, toluene and xylene, ethers such asdimethoxyethane, tetrahydrofuran and dioxane, alcohols such as methanol,ethanol and propanol and aprotic polar solvents such asN,N-dimethylformamide. Among them, it is preferable to use toluene,xylene, tetrahydrofuran or dimethoxyethane therefor. Neither thereaction temperature nor the reaction time is particularly restricted.In general, the reaction is performed at -5° to 150° C., preferably fromroom temperature to the reflux temperature of the solvent, for 1 to 20hours, preferably 2 to 6 hours. The reaction can be advantageouslycarried out by using from 0.5 to 2 mol (preferably from 0.8 to 1.2 mol)of the compound of the formula (II) and from 1 to 4 mol (preferably from1.5 to 3.0 mol) of the sodium alkoxide each per mol of the compoundrepresented by the formula (I).

The compounds represented by the formulae (V) and (VI), which have beenoptionally isolated from each other, are then employed in the step (b).Although the solvent is usually eliminated from these compounds prior tothe use in the step (b), these compounds may be employed in the step (b)as such.

In the step (b) of the above reaction scheme, the compound representedby the formula (v) or (VI) obtained in the step (a) is treated by addingan acid in an appropriate aqueous solvent to thereby give a compoundrepresented by the formula (III) via devinylation, hydrolysis anddecarboxylation. The solvent to be used in this step is not particularlylimited, so long as it exerts no undesirable effect on the reaction.Examples thereof include hydrocarbons such as benzene, toluene andxylene, ethers such as dimethoxyethane, tetrahydrofuran (THF) anddioxane, alcohol is such as methanol, ethanol, propanol and isopropanoland water. Among all, it is preferable to use methanol, ethanol,isopropanol or water therefor.

Examples of the acid to be used in the step (b) include inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid and nitricacid and organic acids such as acetic acid, p-toluenesulfonic acid,benzenesulfonic acid, methanesulfonic acid and trifluoroacetic acid. Itis preferable to use hydrochloric acid, hydrobromic acid or sulfuricacid therefor. Neither the reaction temperature nor the reaction time isparticularly restricted. In general, the reaction is performed at 50° to150° C., preferably from room temperature to the reflux temperature ofthe solvent, for 1 to 10 hours, preferably 1 to 5 hours.

The compound represented by the formula (III) obtained in this step canbe isolated in the form of a salt of the acid employed. The compound(III), which has been optionally isolated, is then employed in the step(c).

In the step (c), the compound (III) obtained in the step (b) is treatedwith a base in an appropriate aqueous solvent to thereby give a compound(IV).

The base to be used in this step is not particularly limited, so long asit exerts no undesirable effect on the reaction. Examples thereofgenerally include alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide, alkali metal carbonates such as sodium carbonateand potassium carbonate, alkali metal phosphates such as sodiumphosphate and potassium phosphate, inorganic bases such as aqueousammonia and anionic ion exchange resins. It is preferable to use sodiumhydroxide or potassium hydroxide therefor. As the solvent, use can bemade of those cited in the step (b) too. The reaction is performed at 0°to 50° C., preferably at room temperature, though the reactiontemperature is not particularly restricted. By regulating the pH valueto 9 to 12, the compound (IV) can be obtained.

For the purpose of reference, it is indicated that the compound (IV)obtained in the step (c) can be given in the form of a salt of an acidwith the use of the compound (III) by treating with the acid in anappropriate aqueous solvent as shown by the step (d). As the solvent andacid to be used in this step (d), use can be made of those cited in thestep (b). Neither the reaction temperature nor the reaction time isparticularly restricted. In general, the reaction is performed at 0° to100° C., preferably 0° to 50° C., for 1 to 17 hours, preferably 1 to 4hours.

The compound obtained by the present invention can be isolated andpurified by conventionally known means for separation and purificationsuch as distillation, recrystallization, silica gel chromatography, etc.

BEST MODE FOR CARRYING OUT THE INVENTION

To further illustrate the present invention in greater detail, thefollowing Examples and Reference Example will be given.

Example 1: Synthesis of 3-nicotinoyl-1-vinyl-2-piperidinone (compound ofthe formula (V))

25.5 g (375 mmol) of sodium ethoxide was added to 250 ml oftetrahydrofuran (THF). While heating under reflux, a solution of 31.25 g(250 mmol) of N-vinylpiperidone and 37.75 g (250 mmol) of ethylnicotinate in tetrahydrofuran (75 ml) was added thereto and theresulting mixture was refluxed for 3 hours. Then, it was cooled to 10°C. or below and 175 ml of a saturated aqueous solution of ammoniumchloride was added. The organic layer was separated and the aqueouslayer was further extracted with 200 ml portions of ethyl acetate twice.The extracts were combined with the above-mentioned organic layer anddried with sodium sulfate. After filtering off the sodium sulfate, thefiltrate was concentrated under reduced pressure and dried. Thus, 52.71g of a mixture of the keto-enol tautomers of the title compound wasobtained (yield: 91.6%). This mixture was added to 150 ml of diisopropylether and stirred at room temperature for 1 hour. After filtering anddrying under reduced pressure, 32.9 g of the title compound (keto-form)was obtained (yield: 57.1%). IR spectrum (KBr) ν_(max) : 1627 cm⁻¹.

NMR spectrum (CDCl₃, internal standard: tetramethylsilane, δ ppm):

1.7-2.4 (4H, m); 3.4-3.6 (2H, m); 4.4-4.6 (3H, m); 7.4-7.6 (2H, m);8.3-9.3 (3H, m).

Example 2: Synthesis of 3-(5-amino-1-pentanoyl)pyridine dihydrochloride(dihydrochloride of compound of the formula (III))

4.6 g (keto-form, 20 mol) of the 3-nicotinoyl-1-vinyl-2-piperidinoneobtained in Example 1 was refluxed in 40 ml of 6N hydrochloric acid for3 hrs. After cooling, the reaction mixture was concentrated underreduced pressure so as to reduce the volume of the solution to about1/10. Then, 46 ml of isopropyl alcohol was added at room temperature andthe resulting mixture was stirred for 4 hours. The precipitate thusformed was taken up by filtration and dried under reduced pressure tothereby give 4.7 g of the title compound (yield: 93.6%). m.p.: 173°-176°C.

IR spectrum (KBr) ν_(max) : 2950 cm⁻¹, 1700 cm⁻¹.

NMR spectrum (DMSO, internal standard: tetramethylsilane, δ ppm):

1.6-1.8 (4H, m); 2.7-2.9 (2H, m); 3.1-3.3 (2H, m); 7.9-8.0 (1H, m);8.0-8.3 (2H, b); 8.7-9.4 (3H, m); 9.4-10.4 (2H, b).

Example 3: Synthesis of 2-(3-pyridyl)-3,4,5,6-tetrahydropyridine(compound of the formula (IV): anabaseine)

9.9 g (mixture of keto-enol tautomers, 43 mmol) of the3-nicotinoyl-1-vinyl-2-piperidinone obtained in Example 1 was dissolvedin 12 ml of tetrahydrofuran and added to 55 ml of 6N hydrochloric acidunder reflux at 80° to 100° C. After stirring at 85° C. for 3 hours, thereaction mixture was cooled to 10° C. or below. Then, the pH value ofthe mixture was adjusted to about 11 by adding a 10M aqueous solution ofsodium hydroxide at 10° to 30° C. The resulting aqueous solution wasextracted with 40 ml portions of dichloromethane thrice and dried withsodium sulfate. After evaporating the dichloromethane under reducedpressure, 6.5 g of the title compound was obtained as an oily residue(yield: 94.5%). NMR spectrum (CDCl₃, internal standard:tetramethylsilane, δ ppm):

1.5-2.0 (4H, m); 2.5-2.7 (2H, m); 3.8-3.9 (2H, m); 7.2-9.0 (4H, m).

Reference Example: Synthesis of 3-(5-amino-1-pentanoyl)-pyridinedihydrochloride (dihydrochloride of compound of the formula (III))

6.5 g (41 mmol) of the 2-(3-pyridyl)-3,4,5,6-tetrahydropyridine obtainedin Example 3 was dissolved in 123 ml of isopropanol. At a temperature of30° C. or below, 6.9 ml of conc. hydrochloric acid was added thereto andthe mixture was stirred at room temperature for 3 hours. Then, thereaction mixture was cooled at 5° C. or below for 2 hours. Theprecipitate thus formed was taken up by filtration, washed withisopropyl alcohol and dried under reduced pressure to thereby give 7.7 gof the title compound (yield: 74.6%).

Comparative Example 1: Synthesis of compound (IV)

In order to compare with the present invention, the compound (IV) wassynthesized in accordance with the method described in Chem. Ber., 69,1082-1085 (1936). Namely, 4.06 g (20 mmol) of N-benzoyl-2-piperidone,3.03 g (20 mmol) of ethyl nicotinate and 8 ml of benzene were introducedinto a flask. Further, 1.84 g (27 mmol) of sodium ethoxide was addedthereto and the resulting mixture was heated under reflux for 5 hours.Then, the reaction mixture was evaporated to dryness. To the obtainedresidue was added 59 ml of conc. hydrochloric acid and the mixture washeated under reflux at 110° C. for 2 hours. The reaction mixture wascooled and a 10M aqueous solution of sodium hydroxide was added theretoat 14° to 30° C. until the pH value reached 10.3. Then, it was extractedwith 60 ml portions of dichloromethane twice. The organic layers werecombined, washed with a saturated aqueous solution of sodium chlorideand then dried with Na₂ SO₄. After filtering off the Na₂ SO₄, thefiltrate was concentrated and the residue was purified by silica gelchromatography (developing solvent: chloroform, ethanol) to thereby give1.87 g of the title compound (yield: 58.4%).

Comparative Example 2:

The procedure of Comparative Example 1 was repeated except for replacingthe benzene employed as the solvent by tetrahydrofuran (THF). Thus, 1.35g of the compound (IV) was obtained (yield: 42.2%).

Comparative Example 3:

The procedure of Comparative Example 1 was repeated except for replacingthe N-benzoyl-2-piperidone employed as the starting material byN-trimethylsilyl(TMS)-2-piperidone. Thus, 0.38 g of the compound (IV)obtained (yield: 23.8%).

Comparative Example 4:

The procedures of Examples and Reference Example were followed exceptfor replacing the-sodium alkoxide employed as the base by sodiumhydride. Thus, 9.14 g of dihydrochloride of the compound (III) wasobtained (yield: 71.8%).

Comparative Example 5:

Under a nitrogen gas stream, 6.25 g (50 mmol) of N-vinylpiperidone and27 ml of tetrahydrofuran were introduced into a flask and cooled to -60°C. Then, 32 ml of a solution of n-butyllithium in hexane (1.6 mol/l) wasadded dropwise thereto at -50° to -60° C. and the resulting mixture wasstirred at the same temperature for 20 minutes. To the solution thusobtained was added dropwise 7.55 g (50 mmol) of ethyl nicotinate at -50°to -60° C. and the resulting mixture was stirred at the same temperaturefor 20 minutes. Then, the reaction mixture was heated and stirred atroom temperature for 5 hours. After the completion of the reaction, 60ml of a saturated aqueous solution of ammonium chloride was added andthe mixture was quenched. After extracting with 70 ml portions of ethylacetate thrice, the extracts were dried with anhydrous sodium sulfate.Then, the sodium sulfate was filtered off and the filtrate wasconcentrated under reduced pressure to thereby give 6.8 g of a residue.This residue was subjected to successive treatments by the same methodsas described in Example 3 and Reference Example. Thus, 0.68 g ofdihydrochloride of the compound (III) was obtained (yield: 5.4%).

Comparative Example 6:

Under a nitrogen gas stream, 3.5 ml (50 mmol) of diisopropylamine and 12ml of tetrahydrofuran were introduced into a flask and cooled to -30° C.Then, 32 ml of a solution of n-butyllithium in hexane (1.6 mol/l) wasadded dropwise thereto at -20° to -30° C. and the resulting mixture wasstirred at the same temperature for 20 minutes to thereby give asolution of lithium diisopropylamide (LDA). This solution was cooled to-60° C. and then a solution of 6.25 (50 mmol) of N-vinylpiperidone in 15ml of tetrahydrofuran was added dropwise thereto at -50° to -60° C. Theresulting mixture was further stirred at this temperature for 20minutes. The resulting solution was treated in the same manner asdescribed in Comparative Example 5 with the use of 7.55 (50 mmol) ofethyl nicotinate. Thus, 3.55 g of dihydrochloride of the compound (III)was obtained (yield: 28.3%).

Tables 1 and 2 show the results of the above Examples and ComparativeExamples.

Table 1 shows a comparison of the yields of the compound (IV) dependingon the N-protecting groups of 2-piperidone and solvents. The yield ofExample means the yield of the compound (IV) obtained from the startingmaterial of Example 1 through the reaction of Example 3.

Table 2 shows a comparison of the yields of dihydrochloride of thecompound (III) depending on bases. The yield of Example means the yieldof dihydrochloride of the compound (III) obtained from the startingmaterial of Example 1 through the reaction of Example 3 followed by thetreatment of Reference Example.

                  TABLE 1                                                         ______________________________________                                                N-Protecting              Yield of                                    Example Group of                  Compound (IV)                               No.     2-Piperidone                                                                            Base      Solvent                                                                             (%)                                         ______________________________________                                        Example vinyl     NaOEt     THF   81.3                                        Comp.   benzoyl   NaOEt     benzene                                                                             54.2                                        Example 1                                                                     Comp.   benzoyl   NaOEt     THF   42.2                                        Example 2                                                                     Comp.   TMS       NaOEt     benzene                                                                             23.8                                        Example 3                                                                     ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                                N-Protecting              Yield of                                    Example Group of                  Compound (III)                              No.     2-Piperidone                                                                             Base     Solvent                                                                             (%)                                         ______________________________________                                        Example vinyl      NaOEt    THF   64.6                                        Comp.   vinyl      NaH      THF   71.8                                        Example 4                                                                     Comp.   vinyl      n-BuLi   THF    5.4                                        Example 5                                                                     Comp.   vinyl      LDA      THF   28.3                                        Example 6                                                                     ______________________________________                                    

In the reaction according to the present invention, no rapid change intemperature was observed and scarcely any side-product was formed. InComparative Example 4, vigorous foaming was observed in the reactiontogether with the heat generation and the evolution of hydrogen gas.

A comparison among the results of Examples and Comparative Examples 1 to3 indicates that the yield can be elevated by using a vinyl group as theprotecting group. Also, a comparison among the results of Examples andComparative Examples 4 to 6 indicate that the yield achieved by usingsodium ethoxide as a base is almost comparable to the yield achievedwith the use of sodium hydride.

INDUSTRIAL APPLICABILITY

The compounds and production processes of the present invention areuseful as production intermediates of pyridine derivatives representedby the following formulae (III) and (IV): ##STR10## which are useful asa remedy for central nervous system diseases such as Alzheimer's diseaseand Parkinson's disease, and methods for producing the same.

We claim:
 1. A compound represented by formula (V): ##STR11## itstautomer and a mixture of the same.
 2. A process for producing acompound represented by the formula (V), its tautomer or a mixture ofthe same as claimed in claim 1, which comprises reactingN-vinylpiperidone represented by formula (I): ##STR12## with anicotinate represented by formula (II): ##STR13## wherein R represents alower alkyl group; in the presence of a sodium alkoxide.
 3. The processfor producing a compound represented by the formula (V), its tautomer ora mixture of the same as claimed in claim 2, wherein said sodiumalkoxide is sodium ethoxide.
 4. The process for producing a compoundrepresented by the formula (V), its tautomer or a mixture of the same asclaimed in claim 2, wherein R in the formula (II) is an ethyl group andsaid sodium alkoxide is sodium ethoxide.